11 β-substituted progesterone analogs

ABSTRACT

A 11β-aryl-19-norprogesterone steroid of the formula: ##STR1## wherein (i) R 1  is H, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, OH, OC(O)CH 3 , or OC(O)R 5 , wherein R 5  is C 2-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl or aryl, R 2  is H, R 3  is H, C 1-4  alkyl, C 2-4  alkenyl or C 2-4  alkynyl, R 4  is H, CH 3 , F or Cl, R 6  is H, (CH 3 ) 2  N, CH 3  O, CH 3  CO, CH 3  S, CH 3  SO, CH 3  SO 2 , and X is O or NOCH 3  ; or 
     (ii) R 1  and R 2  taken together are a carbon-carbon bond and R 3 , R 4 , R 6  and X are as defined above; or 
     (iii) R 1  and R 3  taken together are --CH 2  -- or --N═N--CH 2  --, R 2  is H and R 4 , R 6  and X are as defined above; or 
     (iv) R 2  and R 3  taken together are ═CH 2  and R 1 , R 4 , R 6  and X are as defined above.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates generally to the field of steroids, and inparticular, to new 11β-substituted 19-norprogesterone analogs whichpossess antiprogestational or progestational activity.

2. Discussion of the Background

There have been many prior attempts over the past few decades to preparesteroids with antihormonal activity. These have been reasonablysuccessful where anti-estrogens and anti-androgens are concerned. Thediscovery of effective antiprogestational and antiglucocorticoidsteroids, however, has proved to be a formidable task for the steroidchemist. It has been generally recognized for some years, however, thatantiprogestational steroids would find wide applicability in populationcontrol, while antiglucocorticoids would be extremely valuable in thetreatment of, for example, Cushing's syndrome and other conditionscharacterized by excessive endogenous production of cortisone. In thelast decade largely through the efforts of Teutsch et al of theRoussel-Uclaf group in France, a new series of 19-nortestosteronederivatives has been synthesized with strong affinity for theprogesterone and glucocorticoid receptors and with markedantiprogestational and antiglucocorticoid activity in vivo. Thisimportant discovery revealed the existence of a pocket in theprogesterone/cortisone receptors able to accommodate a large11β-substituent on selected 19-nortestosterone derivatives. By suitableselection of such a substituent steroids with antihormonal propertieswere obtained.

The pioneering studies of Teutsch et al on the synthesis ofantiprogestational and antiglucocorticoid steroids is summarized in arecent review (G. Teutsch in Adrenal Steroid Antagonism. Ed. M. K.Agarwal, Walter de Gruyter and Co., Berlin, 1984. pp. 43-75) describingwork leading to the discovery of RU-38,486 (I), the first steroid ofthis type selected for clinical development. See FIG. 1. RU-38,486 ormefipristone was found to be an effectiveantiprogestational/contragestative agent when administered during theearly stages of pregnancy (IPPF Medical Bulletin 20; No. 5, 1986). Inaddition to these antiprogestational properties, mefipristone had verysignificant antiglucocorticoid activity and was successfully used byNieman et al (J. Clin. Endocrinology Metab. 61:536, 1985) in thetreatment of Cushing's syndrome. In common with the vast majority ofsteroidal hormone analogs, mefipristone additionally exhibits a range ofbiological properties. Thus, for example, it exhibits growth-inhibitoryproperties towards estrogen-insensitive T47Dco human breast cancer cells(Horwitz, Endocrinology 116:2236, 1985). Experimental evidence suggeststhat the metabolic products derived from mefipristone contribute to itsantiprogestational and antiglucocorticoid properties (Heikinheimo et al,J. Steroid Biochem. 26:279, 1987).

There have been a number of attempts by various workers to modify themefipristone structure in order to obtain separation of theantiprogestational activity from the antiglucocorticoid activity. Thus,the Schering group (Steroids 44:349-519, 1984) has described analogs ofmefipristone termed ZK 98.299 (II) and ZK 98.734 (III). See FIG. 1.Mefipristone is the most active antiglucocorticoid steroid relative toits antigestagenic potency while steroid (III) is the least active.Steroid (II) has an intermediate position in this respect.

Comparison of the contragestative properties of these threeantiprogestational steroids (Elger et al, J. Steroid Biochem. 25:835,1986) has not only revealed different endocrinological profiles, but hasindicated the critical importance of the ratio of antiglucocorticoid toantiprogestational activity to the biological activity. It thus seemsinevitable that a series of related structures possessing a gradation ofantiprogestational/antiglucocorticoid properties will need to bedeveloped in order to providecontragestative/antiglucocorticoid/antitumor products designed forspecific clinical situations. Unfortunately, the art has not yet reachedthe stage when accurate predictions of biological properties on thebasis of chemical structures can be made so that a degree of empiricismis unavoidable.

There continues to be a need for the development of new steroids withvarying degrees of antiprogestational and antiglucocorticoid activities.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide newsteroid compounds having antiprogestational and/or antiglucocorticoidalproperties.

Another object of the invention is to provide novel steroids havingprogestational as well as antiprogestational activity.

These and other objects which will become apparent from the followingspecification have been achieved by the present11β-aryl-19-norprogesterone compounds of the formula ##STR2## wherein(i) R¹ is H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, OH, OC(O)CH₃, orOC(O)R⁵, wherein R⁵ is C₂₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl or aryl,R² is H, R³ is H, C₁₋₄ alkyl, C₂₋₄ alkenyl or C₂₋₄ alkynyl, R⁴ is H,CH₃, F or Cl, R⁶ is H, (CH₃)₂ N, CH₃ O, CH₃ CO, CH₃ S, CH₃ SO or CH₃ SO₂and X is O or NOCH₃ ; or (ii) R¹ and R² taken together represent acarbon-carbon bond, and R³, R⁴, R⁶ and X are as defined above; or (iii)R¹ and R³ taken together are --CH₂ -- or --N═N--CH₂ --, R² is H and R⁴,R⁶ and X are as defined above; or (iv) R² and R³ taken together are ═CH₂and R¹, R⁴, R⁶ and X are as defined above.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the invention and many of the attendantadvantages thereof will be readily obtained as the same becomes betterunderstood by reference to the following detailed description whenconsidered in connection with the accompanying drawings, wherein:

FIGS. 1A, 1B and 1C give the respective structures of prior artcompounds ZK 95.890, ZK 98.734 and ZK 98.299; and

FIG. 2 illustrates the structures of the compounds of the presentinvention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Research in this area has dealt with 11β-aryl-19-nortestosterone analogsin which the 17β-position (or the 17β-position in the inverted compoundssuch as III) is substituted by a hydroxyl group. This invention providesfor the first time novel 11β-aryl-19-norprogesterone analogs in whichthe 17β-position is substituted by an acetyl group. The resultingcompounds are generally characterized by strong binding affinity to theprogesterone and glucocorticoid receptors. Research in this series ofstructures, however, is not yet able to predict the nature of thisbiological activity on the basis of structure and binding affinity tothe progesterone and glucocorticoid receptors. Thus in contrast to priorart which teaches that in the 11β-aryl-19-nortestosterone series, an11β-aryl substituent, e.g. 11β-(4-N,N-dimethylaminophenyl), leads toantiprogestational activity, surprisingly in the11β-aryl-19-norprogesterones of the present invention, strong binding tothe progesterone receptor may lead to either antiprogestational orprogestational activity in vivo. Thus the 17α-acetoxy structures IV(FIG. 2) (R¹ =OAc, R² =R³ =H, R⁴ =H or CH₃, R⁶ =Me₂ N, X=O) and the16α-ethyl structures IV (R^(1=R) ² =H, R³ =Et, R⁴ =H or CH₃, R⁶ =Me₂ N,X=O) both exhibit strong binding to the progesterone receptor. Theformer compounds block the action of progesterone when administered invivo, whereas the latter surprisingly show potent progestationalactivity in vivo.

Furthermore in the 19-norprogesterone series there is not always theexpected correlation between binding to the progesterone receptor and invivo activity. Thus the Δ-16 compound IV (R¹,R² =double bond, R³ =R⁴ =H,R⁶ =Me₂ N, X=O) binds relatively weakly to the progesterone receptor,but when used in vivo exhibits strong antiprogestational activity.

The 11β-substituted norprogesterone analogs of the present inventioncomprise compounds having structures A-C shown below. ##STR3##

The compounds having structure A all contain a 16β-hydrogen substituent(R²) and a 17β-acetyl substituent. The 16α substituent (R³) may behydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl or C₂₋₄ alkynyl groups. The 17αsubstituent (R¹) may be methyl, C₂₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,hydroxyl, OC(O)CH₃ (O-acetyl), or OC(O)R⁵, where R⁵ is C₂₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl or aryl. Alternatively, the 17α- and16α-substituents R¹ and R³ taken together are --CH₂ -- or --N═N--CH₂ --.

Preferred compounds having structure A are those in which R⁶ isN,N-dimethylamino or acetyl. Additional preferred compounds are those inwhich R⁴ is hydrogen or methyl and R¹ is acetoxy or C₂₋₆ alkynyl groups.Specific examples of compounds having structure A are17α-acetoxy-6α-methyl-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione,17α-acetoxy-1162-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione,16α-ethyl-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione,16α-ethyl-6β-methyl-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione,17α-ethynyl-118-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione,11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione,11β-(4-acetylphenyl)-19-norpregna-4,9-diene-3,20-dione,17α-acetoxy-11β-(4-acetylphenyl)-19-norpregna-4,9-diene-3,20-dione, and17α-ethynyl-118-(4-acetylphenyl)-19-norpregna-4,9-diene-3,20-dione.

Compounds having structure B exhibit a carbon-carbon double bond betweenC16 and C17. R³, R⁴, R⁶ and X may be any of the groups defined above.Preferred compounds having structure B are compounds in which R⁶ is anN,N-dimethylamino or an acetyl group. Additionally preferred compoundshaving structure B are those in which R³ is H and R⁴ is H or CH₃.Specific examples of such compounds include11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9,16-triene-3,20-dioneand 11β-(4-acetylphenyl)-19-norpregna-4,9,16-triene-3,20-dione.

In the compounds having structure C, R² and R³, taken together, are a═CH₂ group. Preferred examples include compounds in which R¹ is acetoxyor C²⁻⁸ alkynyl, R⁴ is hydrogen or methyl and R⁶ is dimethylamino oracetyl.

Preferred aryl groups for R⁵ in compounds A-C have the formula --C⁶ H₄--R⁶, in which R⁶ has the same meaning as defined above.

Steroids having progestational, antiprogestational and/orantiglucocorticoid activity have use in the control of fertility inhumans and non-human mammals such as primates, domestic pets and farmanimals, and in the treatment of medical conditions in animals or humansin which these activities are beneficial. Thus they may be useful in thetreatment of conditions such as Cushing's syndrome, glaucoma,endometriosis, premenstrual syndrome and cancer in addition to their usein the control of reproduction.

The compounds of the present invention may be administered by a varietyof methods. Thus, those products of the invention that are active by theoral route may be administered in solutions, suspensions, emulsions,tablets, including sublingual and intrabuccal tablets, soft gelatincapsules, including solutions used in soft gelatin capsules, aqueous oroil suspensions, emulsions, pills, lozenges, troches, tablets, syrups orelixirs and the like. Products of the invention active on parenteraladministration may be administered by depot injection, implantsincluding Silastic™ and biodegradable implants, intramuscular andintravenous injections.

Compositions may be prepared according to any method known to the artfor the manufacture of pharmaceutical compositions and such compositionsmay contain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents. Tablets containing the active ingredient in admixture withnontoxic pharmaceutically acceptable excipients which are suitable formanufacture of tablets are acceptable. These excipients may be, forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, such as maize starch, or alginic acid; bindingagents, such as starch, gelatin or acacia; and lubricating agents, suchas magnesium stearate, stearic acid or talc. Tablets may be uncoated ormay be coated by known techniques to delay disintegration and adsorptionin the gastrointestinal tract and thereby provide a sustained actionover a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate alone or with a wax may beemployed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethylene oxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol (e.g.,polyoxyethylene sorbitol mono-oleate), or a condensation product ofethylene oxide with a partial ester derived from fatty acid and ahexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). Theaqueous suspension may also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such assucrose, aspartame or saccharin. Ophthalmic formulations, as is known inthe art, will be adjusted for osmotic pressure.

Oil suspensions may be formulated by suspending the active ingredient ina vegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. The oil suspensionsmay contain a thickening agent, such as beeswax, hard paraffin or cetylalcohol. Sweetening agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of anantioxidant such as ascorbic acid.

Dispersible powders and granules of the invention suitable forpreparation of an aqueous suspension by the addition of water may beformulated from the active ingredients in admixture with a dispersing,suspending and/or wetting agent, and one or more preservatives. Suitabledispersing or wetting agents and suspending agents are exemplified bythose disclosed above. Additional excipients, for example sweetening,flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, a mineral oil, such as liquid paraffin, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan mono-oleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan mono-oleate. Theemulsion may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, such asglycerol, sorbitol or sucrose. Such formulations may also contain ademulcent, a preservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the invention may be in the form of asterile injectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a nontoxic parenterally-acceptable diluent or solvent,such as a solution of 1,3-butanediol. Among the acceptable vehicles andsolvents that may be employed are water and Ringer's solution, anisotonic sodium chloride. In addition, sterile fixed oils mayconventionally be employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid may likewisebe used in the preparation of injectables.

The compounds of this invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperatures and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

They may also be administered by intranasal, intraocular, intravaginal,and intrarectal routes including suppositories, insufflation, powdersand aerosol formulations.

Products of the invention which are preferably administered by thetopical route may be administered as applicator sticks, solutions,suspensions, emulsions, gels, creams, ointments, pastes, jellies,paints, powders, and aerosols.

Products having anti-glucocorticoid activity are of particular value inpathological conditions characterized by excess endogenousglucocorticoid such as Cushing's syndrome, hirsutism and in particularwhen associated with the adrenogenital syndrome, ocular conditionsassociated with glucocorticoid excess such as glaucoma, stress symptomsassociated with excess glucocorticoid secretion and the like.

Products having progestational activity are of particular value asprogestational agents, ovulation inhibitors, menses regulators,contraceptive agents, agents for synchronization of fertile periods incattle, endometriosis, and the like. When used for contraceptivepurposes, they may conveniently be admixed with estrogenic agents, suchas for example as ethynylestradiol or estradiol esters.

Products having anti-progestational activity are characterized byantagonizing the effects of progesterone. As such, they are ofparticular value in control of hormonal irregularities in the menstrualcycle and for synchronization of fertile periods in cattle.

The compounds of the invention may be used for control of fertilityduring the whole of the reproductive cycle. They are of particular valueas postcoital contraceptives, for rendering the uterus inimical toimplantation, and as "once a month" contraceptive agents. They may beused in conjunction with prostaglandins, oxytocics and the like.

A further important utility for the products of the invention lies intheir ability to slow down growth of hormone-dependent cancers. Suchcancers include kidney, breast, endometrial, ovarian cancers, andprostate cancer which are characterized by possessing progesteronereceptors and may be expected to respond to the products of thisinvention. Other utilities of anti-progestational agents includetreatment of fibrocystic disease of the breast. Certain cancers and inparticular melanomas may respond favorably to corticoid/anticorticoidtherapy.

The compounds according to the present invention may be administered toany warm-blooded mammal such as humans, domestic pets, and farm animals.Domestic pets include dogs, cats, etc. Farm animals include cows,horses, pigs, sheep goats, etc.

The amount of active ingredient that may be combined with a carriermaterial to produce a single dosage form will vary depending upon thedisease treated, the mammalian species, and the particular mode ofadministration. For example, a unit dose of the steroid may preferablycontain between 0.1 milligram and 1 gram of the active ingredient. Amore preferred unit dose is between 0.001 and 0.5 grams. It will beunderstood, however, that the specific dose level for any particularpatient will depend on a variety of factors including the activity ofthe specific compound employed; the age, body weight, general health,sex and diet of the individual being treated; the time and route ofadministration; the rate of excretion; other drugs which have previouslybeen administered; and the severity of the particular disease undergoingtherapy, as is well understood by those of skill in the are.

Other features of the invention will become apparent in the course ofthe following description of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES Example 1. Synthesis of6α-Methyl-17β-acetoxy-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione.

6α-Methyl-17α-hydroxy-pregna-1,4-diene-3,20-dione (37.72 g, 0.11 mol)was dissolved in 1 L of freshly distilled tetrahydrofuran and 400 mL ofdry methanol. The solution was cooled in an ice-bath at 0° C. Sodiumborohydride (3.6 g, 0.09 mol) was added in one portion and the mixturewas stirred at 0°-5° C. for 6 h. The reaction mixture was diluted withice water (100 mL) and methanol was removed under reduced pressure. Theresulting thick residue was partitioned between chloroform and water.The chloroform extracts (500 mL=4) was dried over Na₂ SO₄ (anhydrous),filtered and concentrated to give 42 g of crude6α-methyl-17α,20β(α)-dihydroxy-pregna-1,4-dien-3-one. The product wasshown to be a mixture of 20β and 20α-ol in a ratio of 85:15 based on ¹ HNMR analysis. For 20β-ol: ¹ H NMR (CDCl₃ , 60 MHz) δ 0.83 (s, 3,18-CH₃), 1.0 (d, 3, J=6 Hz, 6-CH₃), 1.18 (d, 3, J=6 Hz, 21-CH₃), 4.0 (m,1, 20-H), 6.05 (bs, 1, 4-H), 6.15 (dd, 1, J=12, 2 Hz, 2-H), 7.1 (d, 1,J=12 Hz, 1-H).

Into a flame dried 2 L three-neck round bottom flask equipped withcondenser and addition funnel were added tetrahydrofuran (900 mL),biphenyl (45 g, 0.29 mol) and diphenylmethane (50 mL, 0.285 mol). Themixture was heated to reflux and lithium wire (3.5 g, 0.50 mol) wasadded in one portion. The resulting bluish-green solution of the complexwas heated at gentle reflux for 16 h. An additional 0.5 g of lithiumwire was added to maintain a dark-blue color. The diol (26 g, 0.076 mol)in 170 mL of THF was then added dropwise at such a rate that the bluecolor persisted throughout the addition. The reaction mixture wasrefluxed for an additional 45 min. The excess biphenyl lithium complexwas quenched carefully with methanol in an ice-bath. After dilution withwater (200 mL), THF was removed under reduced pressure and the productwas extracted with CHCl₃ (500 mL×3). The CHCl₃ extracts were combined,dried over sodium sulfate (anhydrous), filtered and concentrated to give118 g of the crude product. The aqueous phase was acidified with HClsolution (10% v/v) and extracted with CHCl₃ (500 mL×2). The CHCl₃extract was dried over Na₂ SO₄ (anhydrous), filtered and concentrated togive 4.5 g of fairly pure 6α-methyl-19-norpregna-1,3,5(10)-triene-3,17α,20β(α) -triol. The 118 g of crude reaction product was purified bySiO₂ column chromatography employing a gradient system (n-hexane-CH₂ Cl₂to 5% acetone-CH₂ Cl₂) to give another 11.2 g of the product:mp=175°-179° C.; ¹ H NMR (250 MHz, CDCl₃) δ 0.82 (s, 3, 18-CH₃), 1.17(d, 3, J=6.4 Hz, 21-CH₃), 1.28 (d, 3, J=6.8 Hz, 6α-CH₃), 4.0 (m, 1,20-H), 6.61 (dd, 1, J=8.5, 2.6 Hz, 2-H), 6.76 (d, 1, J=2.6 Hz, 4-H),7.11 (d, 1, J=8.5 Hz, 1-H);

calcd. mass for C₂₁ H₃₀ O₃ : 330,2095, Found: 330.2197.

Anal. Calcd for C₂₁ H₃₀ O₃ C.: 76.32; H. 9.15. Found: C, 76.82; H, 9.40.

The above crude phenolic product (6.5 g, 0.02 mol) was dissolved in 500mL of methanol and treated with potassium carbonate (15.0 g, 0.10 mol)and iodomethane (20 mL, 0.32 mol). The mixture was stirred at roomtemperature for 48 hours. Methanol was removed under reduced pressure,the residue was diluted with water and acidified with 10% (v/v) HClsolution. The product was extracted with CHCl₃ (300 mL×3). The combinedCHCl₁₃ extract was washed with water, dried over sodium sulfate(anhydrous), filtered and concentrated to give 7.0 g of crude reactionproduct. SiO₂ column chromatography (CH₂ Cl₂ to 5% acetone-CH₂ Cl₂) gavethree fractions: Fraction A (4.0 g) was found to be6α-methyl-3-methoxy-19-norpregna-1,3,5(10)-triene- 17α,20β(α)-diol.Fraction B (0.74 g) was found to be its 20α-hydroxy isomer and FractionC (0.54 g) was the recovered starting phenol. For the 20β-ol:mp=145°-147° C.;

¹ H NMR (250 MHz, CDCl₃) δ 0.82 (s, 3, 18-CH₃), 1.20 (d, 3, J=6.3 Hz,21-CH₃), 1.30 (d, 3, J=7.0 Hz, 6α-CH₃), 2.79 (s, 3, OCH₃, 4.06 (m, 1,20-H), 6.73 (dd, 1, J=8.7, 2.7 Hz, 2-H), 6.82 (d, 1, J=2.7 Hz, 4-H),7.20 (d, 1, J=8.7 Hz, 1-H);

Calcd mass for C₂₂ H₃₂ O₃ : 344.2355. Found 344.2355.

Anal. Calcd for C₂₂ H₃₂ O₃ : C, 77.16; H, 8.83. Found: C, 77.14: H,8.88. For 20α-ol: mp=150°-151° C.;

¹ H NMR (250 MHz, CDCl₃) δ 0.75 (s, 3, 18-CH₃), 1.22 (d, 3, J=6.4 Hz,21-CH₃), 1.30 (d, 3, J =6.9 Hz, 6α-CH₃), 3.79 (s, 3, OCH₃), 3.85 (m, 1,20-H), 6.70 (dd, J=8.7, 2.7 Hz, 2-H), 6.82 (d, 1, J=2.7 Hz, 4-H), 7.20(d. 1. J=8.6 Hz, 1-H).

Liquid ammonia (35 mL) was condensed into a flame dried three-neck roundbottom flask equipped with a Dewar condenser and an additional funnel.Lithium wire (150 mg, 21.6 mmol) was added and the resulting bluishsolution of the Li/NH₃ complex solution was stirred at -78° C. for 1hour. The above methyl ether (380 mg. 1.11 mmol) in 2.0 mL of dry THFand 1.0 mL of t-butanol was added dropwise. The blue color persistedthroughout the addition. The resulting mixture was stirred at -78° C.for an additional 45 minutes and quenched carefully with methanol untilthe blue color faded. Excess ammonia was evaporated under a slow streamof nitrogen. The residue was diluted with water and neutralized with 10%(v/v) HCl solution. The product was extracted with CHCl₃ (50 mL=3). TheCHCl₃ extract was dried over Na₂ SO₄ (anhydrous), filtered andconcentrated to give 380 mg of crude6n-methyl-3-methoxy-19-norpregna-2,5(10)-diene-17α,20β-diol.

¹ H NMR (60 MHz) δ 0.80 (s, 3, 18-CH₃), 1.0 (d, 3, J=6.4 Hz, 6α-CH₃),1.2 (d, J=6 Hz, 21-CH₃), 3.5 (s, 3, 3OCH₃), 4.0 (m, 1, 20-H), 4.6 (bs,1, 2-h).

Without further purification the crude Birch reduction product wasdissolved in 40 mL of methanol and treated with oxalic acid (250 mg in1.5 mL of H₂ O). The mixture was stirred at room temperature for 5 hoursand then solvent removed under pressure and the product extracted withCHCl₃ (50 mL=3). The CHCl₁₃ extract was dried over Na₂ SO₄ (anhydrous),filtered and concentrated to give 350 mg of the crude hydrolyzedproduct. Column chromatography (SiO₂ ; gradient from CH₂ Cl₂ to 5%acetone CH₂ Cl₂) gave 120 mg of6α-methyl-17α,20β-dihydroxy-19-norpregn-5(10)-en-3-one:

¹ H NMR (250 MHz, CDCl₃) δ 0.82 (s, 3, 18-CH₃), 0.99 (d, 3, J=6.9 Hz,6α-CH₃, 1.18 (d, 3, J=6.2 Hz, 21-CH₃), 2.4 (bs, 2, 4-H), 4.0 (m, 1,20-H).

Purified 6α-methyl-17α,20β-dihydroxy-19-norpregna-5(10)-en-3-one (8.31g, 0.025 mol) in 450 mL of dry pyridine was cooled in an ice bath andtreated with pyridinium hydrobromide perbromide (9.30 g, 0.028 mol).After the mixture was stirred at room temperature for 24 hours, it waspoured into ice-cold sodium sulfite solution (500 mL, 10% w/v) andextracted with CHCl₃ (400 mL×3). The CHCl₃ extract was washed withdilute NaHCO₃ solution (5% w/v), dried over Na₂ SO₄ (anhydrous),filtered and concentrated to give 8.5 g of crude reaction product.Column chromatography (SiO₂ ; gradient from CH₂ Cl₂ to 5% acetone in CH₂Cl₂) gave 5.8 g of6α-methyl-17α,20β-dihydroxy-19-norpregna-4,9-dien-3-one: mp=201°-203°C.; ¹ H NMR (250 MHz, CDCl₃), δ 0.97 (s, 3, 18-CH₃); 1.13 (d, J=6.5 Hz,6α-CH₃), 1.19 (d, 3, J=6.2 Hz, 21-CH₃), 4.08 (m, 1, 20-H), 5.8 (bs, 1,4-H), IR (CHCl₃) 3550-3400; (--OH), 1665 (conjugated 3-C═O) cm⁻¹ ; UV(MeOH) λ_(max) 305 nm;

MS Calcd mass for C₂₁ H₃₀ O₃ 330.2195; Found 330.2194;

Anal. Calcd for C₂₁ H₃₀ O₃ ; C, 76.33; H, 9.15.

Found: C, 76.35; H, 9.17.

To a stirred solution of CH₂ Cl₂ (150 ml) and oxalyl chloride (4.5 mL,0.050 mol) was added DMSO (9.0 mL, 0.12 mol) at -60° C. in a dryice-CHCl₃ bath. The mixture was stirred for 5 min and the above compound(5.7 g, 0.017 mol) in 60 mL of methylene chloride was added during 5min; stirring was continued for an additional 30 min. Triethylamine (25mL, 0.175 mol) was added and the reaction mixture was stirred for 15 minand then allowed to warm briefly to room temperature. Water (150 mL) wasthen added and the aqueous layer was reextracted with CH₂ Cl₂ (300mL×2). The organic layers were combined, washed with saturated NaClsolution, dried, filtered and concentrated to give 5.8 g of crudereaction product. Column chromatography (SiO₂ ; CH₂ Cl₂ →10% acetone inCH₂ Cl₂) provided 5.1 g of6α-methyl-17α-hydroxy-19-norpregna-4,9(10)-diene-3,20-dione.Recrystallization from MeOH gave white crystals: mp=230°-232° C.; ¹ HNMR (CDCl₃, 60 MHz) δ 0.78 (s, 3, 18-CH₃), 1.10 (d, 3, J=6.5 Hz,6α-CH₃), 2.25 (s, 3, 21-CH₃), 5.85 (bs, 1, 4H), IR (CHCl₃) 1700(20-C═O), 1665 (conjugated 3-C═O) cm⁻¹ ; UV (MeOH) λ_(max) 305 nm;

Calcd mass for C₂₁ H₂₈ O₃ : 328.2038. Found: 328.2038;

Anal. Calcd for C₂₁ H₂₈ O₃ : C, 76.79; H, 8.59.

Found: C, 76.87; H, 8.64.

To a solution of the above dione (5.8 g, 0.018 mol) in 450 mL of drybenzene was added ethylene glycol (24.0 mL) and p-toluenesulfonic acid(500 mg). The mixture was heated to reflux and a total of 150 mL ofbenzene was distilled off over a period of 3 h. The reaction mixture waspoured over ice water and extracted with ethyl acetate (300 mL×3). Theorganic phase was washed with water, dried over sodium sulfate(anhydrous), filtered and concentrated. The crude residue waschromatographed over SiO₂ (100% CH₂ Cl₂ →2% acetone-CH₂ Cl₂) to give 4.6g of6α-methyl-3,3,20,20-bis-(ethylenedioxy)-19-norpregna-5(10),9(11)-dien-17α-ol-togetherwith 1.0 g of6β-methyl-3,3,20,20-bis-(ethylenedioxy)-19-norpregna-5(10),9(11)-dien-17α-ol.For the 6α-methyl-3,20-diketal: mp=157°-158° C.;

¹ H NMR (CDCl₃, 250 MHz)δ 0.78 (s, 3, 18-CH₃); 0.99 (d, 3, J=6.8 Hz,6α-CH₃), 1.37 (s, 3, 21-CH₃), 3.98 (m, 8, 3,3,20,20-bisketals), 5.57(bs, 1, 11-H),

Calcd mass for C₂₅ H₃₆ O₅ : 416.2563. Found 416.2564;

Anal. Calcd for C₂₅ H₃₆ O₅ : C, 72.08; H, 8.71.

Found: C, 72.14; H, 8.75.

To a solution of the above bisketal (3.2 g, 7.7 mmol) in 75 mL ofmethylene chloride/hexane (1:3) was added m-chloroperbenzoic acid (1.62g, 80%) at 0° C. The mixture was stirred at 0° C. for 10 min and thendiluted with sodium bicarbonate solution (25 mL, 5% w/v). The aqueousphase was extracted with CH₂ Cl₂ (50 mL×2). The combined organic phasewas washed with saturated sodium chloride solution, dried over sodiumsulfate (anhydrous), filtered and concentrated to give 3.4 g of crudeepoxides which consisted mainly of 5α,10α-epoxide as revealed by TLC and¹ H NMR analyses:

¹ H NMR (CDCl₃, 60 MHz) δ 0.75 (s, 3, 18-CH₃), 0.95 (d, 3, J=6.0 Hz,6α-CH₃), 1.30 (s, 3, 21-CH₃), 3.8-4.0 (m, 8, 3, 20-ketals), 5.8 (m, 1,11-H).

The crude epoxide (3.4 g, 7.43 mmol) in dry tetrahydrofuran (25 mL) wasadded dropwise to a Grignard solution ofp-N,N-dimethylaminophenylmagnesium bromide in the presence ofdimethylsulfide cuprous bromide complex (1.8 g. 8.6 mmol). The Grignardmixture was prepared from p-bromo-N,N-dimethylaniline (14.0 g, 70 mmol)and magnesium (1.4 g, 57 mmol) in 150 mL of freshly distilledtetrahydrofuran. After the reaction mixture was stirred at roomtemperature and under nitrogen for 30 min., it was poured into saturatedammonium chloride solution (350 mL) and stirred for 20 min. Extractionwith ethylyacetate (500 mL×3) and evaporation of the solvent gave abluish residue which was first purified by Al₂ O₃ column chromatographyto provide 3.7 g of semi-purified product. Repeated silica gel columnchromatography yielded 1.95 g of6α-methyl-11β-(4-N,N-dimethylaminophenyl)-3,3,20,20-bis(ethylenedioxy)-19-norpregn-9-en-5α-ol.Recrystallization from MeOH/CH₂ Cl₂ gave 1.2 g of needles: mp= 227°-228°C.; ¹ H NMR (250 MHz, CDCl₃) δ 0.46 (s, 3, 18-CH₃), 1.06 (d, 3, J=6.6Hz, 6α-CH₃), 1.38 (s, 3, 21-CH₃), 2.89 (s, 6, --N(CH₃)₂), 3.8-4.0 (m, 8,3, 20-diethylene ketal-H), 4.19 (d, 1, J=6.2 Hz, 11α-H), 6.62 (d, 2,J=8.8 Hz, aromatic H ortho to --N(CH₃)₂), 7.06 (d, 2, J=8.8 Hz,aromatic-H, meta to --N(CH₃)₂);

Calcd for C₃₃ H₄₇ O₆ N: C, 71.58; H, 8.56; N, 2.53.

Found: C, 71.70; H, 8.59; N, 2.51.

Phosphoric acid (85%, 6.5 mL) was added dropwise into acetic anhydride(18 mL) in an ice-bath. The mixture was stirred at 5°-10° C. for 30 minand diluted with acetic acid (20 mL). The resulting mixture was warmedto room temperature and stirred for 1 hour. The above17α-hydroxy-3,20-diketal (680 mg, 1.52 mmol) in dry dioxane (4.0 mL) wasadded to the phosphoric acid/acetic anhydride/acetic acid solution (8.0mL). The mixture turned immediately into a dark-blue solution. Theprogress of the acetylation was carefully monitored with reversephase-HPLC analyses. The reaction was stirred at room temperature for 8hours and diluted with water followed by neutralization with sodiumbicarbonate solution (5% w/v). The product was extracted with ethylacetate (200 mL×3). The organic phase was dried over sodium sulfate(anhydrous), filtered and concentrated to give 750 mg of crude reactionproduct which was purified by Al₂ O₃ column chromatography followed byrepeated reverse-phase column chromatography employing a RP-C8 (Lobarsize B) column and 20% H₂ O in MeOH as the eluting solvent system. Eachindividual fraction collected was monitored by an analytical Zorbax-ODS(4.5 mm×25 cm) column with the same solvent system. The fractionsshowing greater than 95% purity were combined and solvent wasevaporated. Further recrystallization from MeOH/H₂ O provided 110 mg ofwhite crystals of6α-methyl-17α-acetoxy-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione.The major contaminant found both in the mother liquor and in theoverlapping fractions was the 6β-methyl isomer. For the 6α-methylisomer: mp=189°-190.5° C.;

¹ H NMR (250 CDCl₃) δ 0.35 (s, 3, 18-CH₃), 1.24 (d, 3, J=6.5 Hz,6α-CH₃), 2.09 (s, 3, 17α-OAc), 2.12 (s, 3, 21-CH₃), 2.9 (s, 6,--N(CH₃)₂), 4.40 (d, 1, J=7.2 Hz, 11α-H), 5.89 (bs, 1, 4-H), 6.62 (d, 2,J=8.8 Hz aromatic-H, ortho to --N(CH₃)₂), 6.96 (d, 2, J=8.8 Hzaromatic-H, meta to --N(CH₃)₂); Calcd mass for C₃₁ H₃₉ O₄ N: 489.2879.Found 489.2878; IR (CHCl₃), 1730 (17α-C=0), 1720 (20-C=0), 1655(conjugated 3-C=0) cm⁻¹ ; UV (MeOH) λ_(max) 302 nm (dienone), 264 nm(aromatic group);

Anal. calcd for C₃₁ H₃₉ O₄ N: C, 76.04; H, 8.02; N, 2.86.

Found: C, 76.10; H, 8.03; N, 2.84.

EXAMPLE 2. Synthesis of17α-Acetoxy-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione

3-Methoxy-19-norpregna-1,3,5(10),17(20)-tetraene (Krubiner and Oliveto,1966) (1.0 g, 0.0034 mol) in dry pyridine (15 mL) was treated withosmium tetroxide (1.0 g). The resulting dark brown solution was stirredat room temperature for 2 hours and a solution of sodium bisulfite (1.8g in 30 mL H₂ O) and pyridine (20 mL) was added and the mixture wasstirred for an additional 15 min.

The product was extracted with ethyl acetate and the combined organicphase was washed with water, dried over sodium sulfate (anhydrous),filtered and concentrated. Flash chromatography (SiO₂ ; 10% acetone inCH₂ Cl₂) provided 0.82 g of3-methoxy-19-norpregna-1,3,5(10)-triene-17α,20α-diol:

¹ H NMR (CDCl₃, 250 mHz) δ 0.76 (s, 3, 18-CH₃), 1.23 (d, 3, J=6.3Hz,21-H), 3.77 (s, 3, OMe), 3.87 (q, 1, J=6.3 Hz, 20-H), 6.62 (d, 1, J=2.8Hz. 4-H), 6.70 (dd, 1, J=8.5. 2.8 Hz, 2-H), 7.20 (d, 1, J=8.5 Hz, 1-H).

By reduction with lithium in ammonia followed by oxalic acid treatmentas described in Example 1, the above methyl ether (760 mg) was convertedto 3-methoxy-19-norpregna-2,5(10)-diene-17α,20α-diol and thence to17α,20α-dihydroxy-19-nor-5(10)-pregnen-3-one.

¹ H NMR (90 MHz, CDCl₃), δ 0.80 (s, 3, 18-CH₃), 1.2 (d, 3, J=6.5 Hz.21-H), 2.4 (bs, 2, 4-H), 4.0 (m, 1, 20-H).

Pyridinium hydrobromide perbromide (1.5 mmol) as in Example 1, convertedthis compound to 230 mg of17α,20(α)-dihydroxy-19-norpregna-4,9-dien-3-one.

¹ H NMR (CDCl₃, 90 MHz) δ 0.95 (s, 3, 18-CH₃), 1.15 (d, 3, J=6.5 Hz,21-H), 4.1 (m, 1, 20-H), 5.7 (s, 1, 4-H).

Oxidation of the above diol (210 mg) with oxalyl chloride anddimethylsulfoxide as in Example 1 gave17α-hydroxy-19-norpregna-4,9-diene-3,20-dione:

¹ H NMR (CDCl₃, 90 MHz) δ 0.87 (s, 3, 18-CH₃), 2.25 (s, 3, 21-H), 5.70(bs, 1, 4-H); IR (CHCl₃) 1700 (20-C=O), 1665 (conjugated 3-C=O) cm⁻¹.This compound was converted to 190 mg of3,3,20,20-bis-(ethylenedioxy)-19-norpregna-5(10),9(11)-dien-17α-ol bythe procedure described in Example 1:

¹ H NMR (CDCl₃, 90 MHz) δ 1.35 (s, 3, 21-H), 0.80 (s, 3, 18-CH₃), 3.98(m, 8, 3,20-ketals), 5.6 (bs, 1, 11-H).

The above bisketal (175 mg) was epoxidized with meta-chloroperbenzoicacid by the procedure of Example 1 to yield crude5α,10α-epoxy-3,3,20,20-bis-(ethylenedioxy)-19-norpregn-9(11)-en-17α-ol(25) which underwent copper catalyzed Grignard addition as in Example 1to provide 100 mg of3,3,20,20-bis(ethylenedioxy)-11β-(4,N,N-dimethylaminophenyl)-19-norpregn-9-ene-5α,17α-diol:

¹ H NMR (CDCl₃, 90 MHz) δ 0.46 (s, 3, 18-CH₃), 1.38 (s, 3, 21-H), 2.89(s, 6, --N(CH₃)₂), 3.8 (m, 8, 3,20-ketals), 4.78 (bt, 1, 11α-H), 6.6-7.1(m, 4, aromatic-H).

Treatment of this compound with acetic anhydride/phosphoric acid asdescribed in Example 1 yielded17α-acetoxy-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dionewhich was recrystallized from MeOH/H₂ O to give 25 mg of the finalproduct: mp=118°-121° C.; ¹ H NMR (CDCl₃, 250 MHz) δ 0.36 (s, 3,18-CH₃), 2.09 (s, 3, 17α-OAc), 2.13 (s, 3, 21-CH₃), 2.9 (s, 6,--N(CH₃)₂), 4.39 (d, 1 J=7.0 Hz, 11α-H), 5.77 (s, 1, 4-H), 6.6 (d, 2,J=8.6 Hz, aromatic ortho-H to --N(CH₃)₂), 6.9 (d, 2, J=8.6 Hz, aromaticmeta-H to N(CH₃)₂ ; IR (CHCl₃) 1730 (20-C=O), 1660 (3-conjugated C=0)cm⁻ 1 ; UV (MeOH), λ_(max), 261 nm;

Anal. Calcd. for C₃₀ H₃₇ NO₄ : C, 75.76; H, 7.84; N, 2.94.

Found: C, 74.18; H, 7.75; N, 2.81.

EXAMPLE 3. Synthesis of6α-Methyl-16α-ethyl-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione

6α-Methyl-3-methoxy-19-norpregna-1,3,5(10)-triene-17α,20β-diol (900 mg,2.6 mmol) in 30 mL of THF was treated with H₅ IO₆ solution (400 mg in 10mL THF). The reaction mixture was stirred at room temperature for 45 minand filtered through a short neutral alumina column. The filtrate andTHF washings were combined and concentrated to give 750 mg of product.Recrystallization from methanol gave 450 mg of 3-methoxy-6α-methyl-1,3,5(10)estratrien-17-one: mp=108°-109° C.;

¹ H NMR (CDCl₃, 90 MHz) δ 0.88 (s, 3, 18-CH₃), 1.3 (d, 3, J=6.5 Hz,6α-Me), 3.75 (s, 3, 3-OMe), 6.8-7.2 (m, 3, aromatic H);

IR (CHCl₃) 1740 cm⁻¹ (17-C=0);

Anal. calcd for C₂₀ H₂₆ O₂ : C, 80.5; H, 8.78.

Found: C, 80.59; H. 8.80.

A solution of the above 6α-methylestrone-3-methyl ether (5.2 g. 0.017mol) in dry toluene was added rapidly to a stirred solution ofethylidenetriphenylphosphorane freshly prepared from 6.3 g of NaH in 100mL of DMSO and ethyltriphenylphosphonium iodide (54.8 g, 0.13 mol). Thereaction mixture was stirred at 60° C. for 18 hours and was then pouredover ice. The product was taken up with ethyl acetate. The combinedorganic-phase was dried over sodium sulfate, filtered, and concentratedto give 8.5 g of crude product which was purified by SiO₂ columnchromatography (hexane - CH₂ Cl₂, 1:1) to give 4.8 g of3-methoxy-6α-methyl-19-norpregna-1,3,5(10),17(20)-tetraene.

¹ H NMR (CDCl₃, 90 MHz) δ 4 0.89 (s, 3, 18-CH₃): 1.3 (d, 3, J=6.5 Hz,6α-CH₃), 1.6 (d, 3, J=7 Hz, 21-H), 3.8 (s, 3, OMe), 5.1 (m, 1, 20-H),6.8-7.2 (m, 3, aromatic-H); IR (CHCl₃), no C=0.

A solution of the above olefin (500 mg, 1.61 mmol) and hematoporphyrin(22 mg) in 20 mL of pyridine was treated with a fine stream of oxygenwhile being illuminated with a 22 W fluorescent lamp. After 4.5 h, 5 mLof acetic anhydride was added and the reaction mixture was allowed tostand at room temperature for 45 min and was then heated at 60° C. foradditional 30 min. After dilution with water, the product was extractedwith methylene chloride and the organic phase washed thoroughly with 1NHCl and then with 5% sodium bicarbonate solution. After drying, themethylene chloride solution was slurried with 15 g of neutral aluminaoxide and filtered. The concentrated crude reaction product was furtherpurified by SiO₂ column chromatography (15% acetone in CH₂ Cl₂) toprovide 350 mg of3-methoxy-6α-methyl-19-norpregna-1,3,5(10),16-tetraen-20-one:mp=106°-109° C.;

¹ H NMR (CDCl₃, 90 MHz), δ 0.90 (s, 3, 18-CH₃), 1.29 (d, 3, J=6.5 Hz,6α-CH₃), 2.23 (s, 3, 21-H), 3.75 (s, 3, OMe), 6.7 (m, 3, 2, 4 & 16-H),7.15 (d, 1, J=7 Hz, 1-H): IR (CHCl₃) 1670 (conjugated 20-C=0) cm⁻¹ .

Ethylmagnesium bromide (12.5 mL, 25 mmol) 2 M in THF was added to asuspension of Me₂ S.CuBr complex (2.4 g, 0.0177 mol) in 80 mL of THF at0° C. under N₂. The resulting blue solution of the complex was stirredat 0° C. for 20 min and then was added to a cold solution of the abovetetraene (1.5 g, 0.0046 mol) in 40 mL of THF. The reaction mixture wasstirred for 30 min at 0° C. and then diluted with 1 N HCl solution (15mL). The product was extracted with ethyl acetate. The organic phase wasdried, filtered and concentrated to give 2.0 g of crude reactionproduct. Column chromatography (SiO₂ ; 2% acetone in CH₂ Cl₂ ) provided1.5 g of3-methoxy-6α-methyl-16α-ethyl-19-norpregna-1,3,5(10)-trien-20-one;

¹ H NMR (CDCl₃, 250 MHz)δ 7.18 (d, 1, J=8.6 Hz, 1-H), 6.75 (m, 2, 2δ4-H), 3.78 (s, 3, OMe), 2.15 (s, 3, 21-H), 1.30 (d, 3, J=6.8 Hz,6α-CH₃), 0.85 (t, 3, J=7 Hz, 16-CH₂ CH₃), 0.65 (s, 3, 18-CH₃); IR(CHCl₃) 1702 (20-C=0) cm⁻¹.

The above 20-keto compound (7.0 g, 0.020 mol) in THF (250 mL) andmethanol (80 mL) was cooled to 0° C. in an ice bath and treated withsodium borohydride (1.0 g, 0.027 mol). The mixture was stirred at 0° C.for 6.5 hours and was then poured carefully into crushed ice. Theproduct was extracted with ethyl acetate. The organic extract was dried,filtered and concentrated to give 7.3 g of crude product which waspurified by SiO₂ column chromatography (2% acetone in CH₂ Cl₂ ) toprovide 6.8 g of3-methoxy-6α-methyl-16α-ethyl-19-norpregna-1,3,5(10)-trien-20.beta.(α)-ol:

¹ H NMR (CDCl₃, 250 MHz)δ 0.82 (s, 3, 18-CH₃), 0.90 (t, 3, J=7.2 Hz,16-CH2CH₃), 1.22 (d, 3, J=6.3 Hz, 6α-CH₃), 1.30 (d, 3, J=6.8 Hz, 21-H),2.9 (m, 1, 20-H), 3.78 (s, 3, 3-OMe), 6.7 (dd, 1, J=8.5, 2.7 Hz, 2-H),6.8 (d, 1, J=2.7 Hz, 4-H), 7.20 (d, 1, J=8.5 Hz, 1-H).

By the lithium in liquid ammonia procedure of Example 1, the abovesteroid (4.0 g. 0.0113 mol) was converted to 3.95 g of crude3-methoxy-6α-methyl-16α-ethyl-19-norpregna-2,5(10)-dien-20.beta.(α)-olwhich upon treatment with oxalic acid by the procedure in Example 1provided 2.85 g of6α-methyl-16α-ethyl-20β(α)-hydroxy-19-nor-5(10)-pregnen-3-one: ¹ H NMR(CDCl₃, 250 MHz)δ 0.82 (s, 3, 18-CH₃), 0.89 (t, 3, J=7.0 Hz, 16-CH₂CH₃), 1.0 (d, 3, J=6.9 Hz, 6α-CH₃), 1.20 (d, 3, J=6.2 Hz, 21-H), 3.8 (m,1, 20-H).

Treatment of the latter (220 mg) with pyridinium hydrobromide perbromideby the procedure of Example 1 provided 22 mg of 20α-isomer and 150 mg of20α-isomer of20-hydroxy-6α-methyl-16α-ethyl-19-norpregna-4,9-dien-3-one. For 208-ol;

¹ H NMR (CDCl₃, 250 MHz)δ 0.88 (t, 3, J=7.0 Hz, 16-CH₂ CH₃), 0.97 (s, 3,18-CH₃), 1.15 (d, 3, J=6.5 Hz, 6α-CH₃), 1.22 (d, 3, J=6.2 Hz, 21-H), 3.8(m, 1, 20-H), 5.8 (s, 1, 4-H): IR (CHCl₃) 3400 (-OH), 1660 (conjugated3-C=0), cm⁻¹ ;

Anal. Calcd. for C₂₃ H₃₄ O₂ C, 80.65; H. 10.00.

Found: C, 79.36; H, 9.95. For 20α-ol:

¹ H NMR (CDCl₃, 250 MHz), δ 0.86 (s, 3, 18-CH₃), 0.91 (t, 3, J=7.2 Hz,16-CH₂ CH₃), 1.15 (d, 3, J=6.5 Hz, 6α-CH₃), 1.26 (d, 3, J=6.2 Hz, 21-H),3.8 (m, 1, 20-H), 5.8 (s, 1, 4-H).

Oxidation of the above 20-ol (230 mg) with oxalyl chloride anddimethylsulfoxide by the procedure in Example 1 afforded 165 mg of6α-methyl-16α-ethyl-19-norpregna-4,9-diene-3,20-dione: mp=118°-119° C.;

¹ H NMR (CDCl₃, 250 MHz)δ 0.80 (s, 3, 18-CH₃), 0.82 (t, 3, J =7.1 Hz,16-CH₂ CH₃), 1.15 (d, 3, 6.5 Hz, 6α-CH₃), 2.15 (s, 3, 21-H), 5.8 (s, 1,4-H): IR (CHCl₃), 1705 (20C-C=0), 1665 (conjugated 3-C=0) cm⁻¹ ;

Anal. calcd. for C₂₃ H₃₂ O₂ : C, 81.13; H, 9.47.

Found: C, 81.01; H, 9.48.

This latter compound (410 mg, 1.2 mmol) was converted with ethyleneglycol and p-toluenesulfonic acid by the procedure of Example 1 to3,3,20,20-bis-(ethylenedioxy)-6α-methyl-16α-ethyl-19-norpregna-5(10),9(11)-diene(320 mg): ¹ H NMR (CDCl₃, 90 MHz) δ 0.80 (s, 3, 18-CH₃), 0.85 (t, 3, J=7Hz, 16-CH₂ CH₃), 1.1 (d, 3, J=6.5 Hz, 6α-CH₃),.2.1.(s,.3, 21H), 3.8-4.0(m, 8, 3,20-ketals), 5.5 (bs, 1, 11-H).

Epoxidation of the bisketal (305 mg. 0.71 mmol) with m-chloroperbenzoicacid (220 mg, 1.28 mmol) followed by the copper catalyzed Grignardaddition procedure of Example 1 gave 1.2 g of dark blue residuecontaining3,3,20,20-(ethylenedioxy)-6α-methyl-16α-ethyl-11(-(4-N,N-dimethylaminophenyl)-19-nor-9-pregnen-5α-ol.

Without further purification, the above material was treated with 70%aqueous acetic acid and then heated at 50° C. for 40 min. The reactionmixture was poured into ice water and neutralized with 10% (w/v) NaHCO₃solution. The product was extracted with CH₂ Cl₂, dried over sodiumsulfate (anhydrous), filtered and concentrated to give 240 mg of darkblue solid. Column chromatography (SiO₂ ; 5% acetone-CH₂ Cl₂ ) provided42 mg of a single spot (TLC) material. An HPLC analysis (Zorbax-ODS 4.6mm×25 cm. 15% H₂ O in MeOH) showed that the product consisted of 6α and6β-methyl isomers in an approximate ratio of 2:1. A preparative Rp-C18column chromatography (20% H₂ O in MeOH) provided 7.0 mg of6α-methyl-16α-ethyl-118-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dioneand 2.5 mg of68-methyl-16α-ethyl-118-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione,together with 15 mg of unresolved mixture. For 6α-methyl compound:mp=95°-98° C.;

¹ H NMR (CDCl₃, 250 MHz)δ 0.36 (s, 3, 18-CH₃), 0.82 (t, 3, J=7.2 Hz,16-CH_(hd) CH₃), 1.22 (d, 3, J=6.5 Hz, 6α-CH₃), 2.16 (s, 3, 21-H), 2.9(s, 6, N(CH₃)₂), 4.32 (d, 1, J=6.7 Hz, 11α-H), 5.88 (s, 1, 4-H), 6.6 (d,2, J=8.7 Hz, aromatic-H ortho to N(CH₃)₂), 6.98 (d, 2, J=8.7 Hz,aromatic-H meta to N(CH₃)₂). IR (CHCl₃) 1702 (20-C=0), 1660 (conjugated3-C=0) cm¹ ; UV (MeOH) λ_(max) 301, 260 nm;

MS calcd. 459.3137.

Found: 459.3141;

Anal. calcd. for C₃₁ H₄₁ NO₂ ; C, 80.99; H, 8.92; N, 3.04.

Found: C, 80.18; H, 9.02; N, 2.94. For the 6β-methyl isomer:

¹ H NMR (CDCl₃, 250 MHz)δ 0.39 (s, 3, 18-CH₃), 0.82 (t, 3, J=7.2 Hz,16-CH₂ CH₃), 1.28 (d, 3, J=7.1 Hz, 6β-CH₃), 2.17 (s, 3, 21-H), 2.9 (s,6, N(CH₃)₂), 4.33 (d, 1, J=6.7 Hz, 11α-H), 5.78 (s, 1, 4-H), 6.6 (d, 2,J=8.7 Hz, aromatic-H ortho to N(CH₃)₂), 6.98 (d, 2, J=8.7 Hz, aromatic-Hmeta to -N(CH₃)₂).

Example 4. Synthesis of16α-Ethyl-118-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione.

A solution of sodium hydride (0.27 g, 11.3 mmol) in anhydrous dimethylsulfoxide (15 mL) was heated at 75° C. for 1 hour. The reaction mixturewas then cooled to room temperature and a solution of ethyltriphenylphosphonium iodide (4.6 9, 11.3-mmol) in dimethyl sulfoxide (10mL) was slowly added. After stirring at room temperature for 15 min, asolution of3,3-ethylenedioxy-118-(4-N,N-dimethylaminophenyl-5α-hydroxyestr-9-en-17-one(prepared according to Cook et al, U.S. patent application serial No.908,288 (1.0 g, 2.2 mmol) in anhydrous toluene (25 mL) was addeddropwise, and the reaction mixture was subsequently heated at 80° C. for2 hours. The solution was cautiously poured into ice water (250 mL) andextracted with methylene chloride (3×150 mL). The combined extracts werewashed with water (2 x 50 mL) and brine. Removal of the dried (Na₂ SO₄)solvent in vacuo yielded the crude product which was purified by elutionfrom silica gel (50 g) using 1:1 ether-hexane containing 0.1% Et₃ N togive 0.69 g (68%) of3,3-ethylenedioxy-11α-(4-N,N-dimethylaminophenyl)-19-norpregna-9,17(20)-dien-5α-l:mp=174°-177° C.; IR (CHCl₃) 3600 cm⁻¹ ;

¹ H NMR (250 MHz, CDCl₃)δ 0.56 (s, 3, 18-H), 2.91 (s, 6, NMe₂), 3.98 (m,4, OCH₂ CH₂ O), 4.19 (m, s, 11-H), 4.29 (s, 1, 5-OH), 5.08 (m, 1, 20-H),6.50 (d, J=9 Hz, 2, ArH ortho to NMe₂), 7.09 (d, J=9 Hz, 2, ArH meta toNMe₂).

Mass spectrum: m/z required for C₃₀ H₄₁ NO₃ 463.3086.

Found: 463.3085.

Anal. Calcd for C₃₀ H₄₁ NO₃ C, 77.71; H, 8.91; N, 3.02.

Found: C, 77.45; H, 8.93; N, 2.95.

Oxygen gas was slowly bubbled through a solution of the above olefin(0.33 g. 0.7 mmol) and hematoporphyrin (15 mg) in pyridine (7 mL), whilethe solution was irradiated with a fluorescent lamp (25 w) placed 7 cmfrom the reaction flask. After 3 days, the bubbling of oxygen wasdiscontinued. To this reaction mixture was then added acetic anhydride(3 mL), and the solution stirred at room temperature for 2 hours. Thesolvents were then removed in vacuo at room temperature, and the residueeluted from silica gel (50 g) using 2% acetone in methylene chloridecontaining 0.1% Et₃ N to give 140 mg of unchanged starting material.Continued elution with 4% acetone in methylene chloride containing 0.1%Et₃ N yielded3,3-ethylenedioxy-118-(4-N,N-dimethylaminophenyl)-5α-hydroxy-19-norpregna-9,16-dien-20-one(55 mg, 30% based on recovered starting material) as crystals;mp=225-228° C.;

IR (CHCl₃) 3600, 1675 cm⁻¹ ;

¹ H NMR (250 MHz, CDCl₃)δ 0.59 (s, 3, 18-H), 2.24 (s, 3, 21-H), 2.90 (s,6, NMe₂), 3.98 (m, 4, OCH₂ CH₂ O), 4.18 (m, 1, 11-H), 4.37 (s, 1, 5-OH),6.65 (d, J=9 Hz, 2, ArH ortho to NMe₂), 6.67 (apparent s, 1, 16-H), 7.10(d, J=9 Hz, 1, ArH meta to NMe₂).

Mass spectrum: m/z required for C₃₀ H₃₉ NO₄ (M⁺ -18); 459.2773.

Found: 459.2774.

Anal. Calcd for C₃₀ H₃₉ NO₄ 1/4H₂ O: C, 74.88; H, 8.24; N, 2.90.

Found: C, 74.72; H, 8.31; N, 2.86.

To a cold (0° C.), stirred suspension of copper bromide-dimethyl sulfidecomplex (120 mg, 0.58 mmol) in anhydrous tetrahydrofuran (1 mL) wasslowly added 0.4 mL (2.0 molar, 0.8 mmol) of ethylmagnesium bromide intetrahydrofuran. After stirring at 0° for 0.5 h, the Grignard complexwas rapidly added to a cold (0° C.), stirred solution of the aboveunsaturated ketone (16 mg, 0.034 mmol) in tetrahydrofuran (0.5 mL).After stirring at 0° C. for 2 h, the reaction mixture was added dropwiseto a cold (0° C.), rapidly stirred solution of 3 N hydrochloric acid (1mL). After stirring at room temperature for 2 h, the mixture was pouredinto a saturated solution of sodium bicarbonate (10 mL) and extractedwith ethyl acetate (3×25 mL). The combined extracts were washed withwater (2×50 mL) and brine. Removal of the dried (Na₂ SO₄) solvent invacuo yielded the crude product which was purified by elution from areverse phase C-8 column (size B, E. M. Merck) using 85% aqueousmethanol to yield 11 mg (80%) of16α-ethyl-11(-(4-N,N-dimethylaminophenyl)-19-norpregna4,9-diene-3,20-dioneas off-white crystals; mp=168°-171° C.;

IR (CHCl₃) 1720, 1680 cm⁻¹ ;

¹ H NMR (250 MHz, CDCl₃)δ 0.36 (s, 3, 18-H), 0.82 (t, 3, J=7 Hz, CH₂CH₃), 2.16 (s, 3, 21-H), 2.91 (s, 6, NMe₂), 4.32 (m, 1, 11-H), 5.76 (s,1, 4-H), 6.64 (d, J=9 Hz, 2, ArH ortho to NMe₂), 6.98 (d, J=9 Hz, 2, ArHmeta to NMe₂). Mass spectrum: m/z required for C₃₀ H₃₉ NO₂ ; 445.2981.

Found: 445.2977. Anal. Calcd for C₃₀ H₃₉ NO₂ C, 80.85 H, 8.82; N, 3.14.Found: C, 80.75; H, 8.85; N, 3.09.

Example 5, Synthesis of11β-(4-N,N-Dimethylaminophenyl)-19-norpregna-4,9,16-triene-3,20-dione.

To a cold (0° C.) stirred solution of hydrochloric acid (3 N, 1 mL) wasslowly added a solution of3,3-ethylenedioxy-11α-(4-N,N-dimethylaminophenyl)-5α-hydroxy-19-norpregna-5,16-dien-20-one(23 mg, 0.05 mmol) in tetrahydrofuran (2 mL). After being stirred atroom temperature for 2 h, the reaction mixture was poured into asaturated solution of sodium bicarbonate (10 mL) and extracted withmethylene chloride (3×20 mL). The combined extracts were washed withwater (2×20 mL) and brine. Removal of the dried (Na₂ SO₄) solvent invacuo gave the crude product, which was purified by elution from silicagel (0.5 g using 1% acetone-methylene chloride containing 0.1% Et₃ N) toyield 12 mg (50%) of118-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9,16-triene-3,20-dione asa foam;

IR (CHCl₃) 1675 cm⁻¹ ;

¹ H NMR (250 MHz, CDCl₃)δ 0.66 (s, 3, 18-H), 2.26 (s, 3, 21-H), 2.91 (s,6, NMe₂), 4.28 (m, 1, 11-H), 5.75 (s, 1, 4-H), 6.60 (d, J=9 Hz, 2, ArHortho to NMe₂), 6.68 (apparent s, 1, 16-H), 7.06 (d, J=9 Hz, 2, ArH metato NMe2)

Mass-spectrum: m/z required for C₂₈ H₃₃ NO₂ ; 415.2511.

Found: 415.2513.

Example 6. Synthesis of118-(4-N,N-Dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione.

3,3-Ethylenedioxy-118-(4-N,N-dimethylaminophenyl-5α-hydroxy-19-norpregna-9,16-diene-3,20-dionein ethanol solution was reduced with hydrogen in the presence of 5%palladium on charcoal. After one mole of hydrogen per mole of steroidwas taken up, the solution was filtered and treated with hydrochloricacid in ethanol as described in Example 1. Evaporation left a residuewhich was purified by chromatography to yield11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione.

Example 7. Synthesis of11β-(4-N,N-Dimethylaminophenyl)-19-norpregna-4,9,17(20)-trien-3-one.

3,3-Ethylenedioxy-11α-(4-N,N-dimethylaminophenyl)-19-norpregna-9,17(20)-dien-5α-olwas treated with hydrochloric acid in ethanol as described in Example 1and purified by chromatography to yield118-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9,17(20)-trien-3-one.

Example 8. Synthesis of11α-(4-acetylphenyl-19-norpregna-4,9,16-triene-3,20-dione.

By the procedure described in Example 1 for:.the synthesis of6α-methyl-11(-(4-N,N-dimethylaminophenyl)-3,3,20,20-bis(ethylenedioxy}-19-norpregn-9-ene-5α,17α-diolfrom6α-methyl-3,3,20,20-bis(ethylenedioxy)-19-norpregna-5(10),9(11)-dien-17α-ol,but substituting 2-(4-bromomagnesiumphenyl)-2,5,5-trimethyl-1,3-dioxanefor p-N,N-dimethylaminophenylmagnesium bromide,3,3-(ethylenedioxy)estra-5(10),9(11)-dien-17-one was converted to3,3-ethylenedioxy-5α-hydroxy-11β-[4-(2,5,5-trimethyl-1,3-dioxan-2-yl)phenyl]estr-9-en-17-one.The latter compound was subjected to the procedures of Example 4 forconverting 3,3-ethylenedioxy-11β-(4-N,N-dimethylaminophenyl)-5α-hydroxy-9-estren-17-one to3,3-ethylenedioxy-11β-(4-N,N-dimethylaminophenyl)-5α-hydroxy-19-norpregna-9,16-dien-20-onefollowed by acid hydrolysis as described in Example 5 to yield118-(4-acetylphenyl)-19-norpregna-4,9,16-triene-3,20-dione, m.p. around194°-197° C.

Mass spectrum: m/z required for C₂₈ H₃₀ O₃ : 414.2195.

Found: 414.2189.

Example 9. In Vitro Binding to Receptors

The in vitro activity of the subject compounds was determined bymeasuring the binding affinities (RBA) of these compounds relative toprogesterone for the progesterone receptor in the cytosol obtained fromestrogen-primed immature rabbit uterus and by measuring the RBA relativeto dexamethasone for the glucocorticoid receptor from thymus ofadrenalectomized rats. These assays were carried out by the proceduresof J. R. Reel et al., Fertility and Sterility, 31, 552 (1979)(progesterone) and G. P. Chrousos et al., Endocrinology, 107, 472 (1980)(glucocorticoid). The results are presented in Table 1.

                  TABLE 1                                                         ______________________________________                                        RELATIVE RECEPTOR BINDING ACTIVITY                                             ##STR4##                                                                     Compound     Progestin                                                                              Glucocort,                                              R.sub.1                                                                             R.sub.2                                                                              R.sub.3  RBA.sup.a                                                                            RBA.sup.b                                                                            P-RBA/G-RBA.sup.c                         ______________________________________                                        OAc   H      H       47     198     0.24                                      OAc   H      α-CH.sub.3                                                                      43     242     0.18                                      OAc   H      β-CH.sub.3                                                                       15     ND      --                                        OH    H      H       15      41     0.37                                      OH    H      α-CH.sub.3                                                                      46     175     0.26                                      H     Et     H       80     124     0.65                                      H     Et     α-CH.sub.3                                                                      61     246     0.42                                      H     Et     β-CH.sub.3                                                                       48     106     0.45                                      Δ.sup.16                                                                         H        8       ND      --                                          ______________________________________                                         .sup.a Relative ability to displace tritiumlabeled progesterone from the      receptor in uterine cytosol from estrogenprimed immature female rabbits a     compared with progesterone (=100).                                            .sup.b Relative ability to displace tritiumlabeled dexamethasone from the     receptor of the thymus of adrenalectomized rats as compared to                dexamethasone (=100).                                                         .sup.c Ratio of RBA values for progesterone receptor (PRBA) to                glucocorticoid receptor (GRBA).                                          

Example 10. In Vivo Antiprogestational Activity

The antiprogestational activity of the compounds was studied after bothintrauterine and oral administration. In each case the compound wastested for its ability to inhibit the endometrial response due tosubcutaneous administration of progesterone to estrogen-primed immaturefemale rabbits. The methodology used for the intrauterine test has beendescribed by D. A. McGinty et al. See Endocrinology, 24, 829 (1939). Fororal administration of test compounds, the method used was analogous tothat of Clauberg. See Clauberg, Zentr. Gynakol., 54, 2757 (1930) asmodified by McPhail J. Physiol. (London), 83, 145 (1935).

The results of the intrauterine tests are given in Table 2. Each activecompound was characterized by a dose-related ability to block theprogestational effect of simultaneously administered progesterone. Whenthe percent inhibition was plotted versus the log of the dose, linearrelationships were obtained. Linear regression analysis permittedcalculation of the ED₅₀ and ED₉₀ values (the doses required for 50% and90% inhibition of the progesterone effect, respectively). The actualdose which gave 90% or more inhibition is also given, although thisvalue is probably less accurate than the calculated values which arebased on the dose-response line. Very unexpectedly, these results do notcorrelate well at all with the in vitro binding studies. Since theintrauterine administration bypasses most of the drug-metabolizingsystems of the body, especially the liver, intrinsic activity isexpected to correlate reasonably well with binding activity to thereceptor, according to currently held hypotheses regarding receptorbinding. However although the 17α-acetoxy compounds bind well and alsoexhibit potent antiprogestational activity, the Δ-16 compound had evenmore potent activity even though its RBA was less than one-fifth of thevalue of the 17α-acetoxy compounds. Even more surprising was the lack ofantiprogestational activity of the 16α-ethyl compounds, even though theyexhibited the strongest binding to the progesterone receptor.

The 17α-acetoxy compounds also exhibited strong antiprogestationalactivity when given by the oral route, as is shown in Table 3 for17α-acetoxy-6α-methyl-11α-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione.

                  TABLE 2                                                         ______________________________________                                        SUMMARY OF ANTI-MCGINTY ACTIVITY                                               ##STR5##                                                                     Compound          ED.sub.50                                                                             ED.sub.90                                           R.sub.1    R.sub.2                                                                              R.sub.3  (μg).sup.a                                                                       (μg).sup.a                                                                       ED.sub.90 (μg).sup.b                ______________________________________                                        8a     OAc     H      H     0.41  1.2    2.0                                  8b     OAc     H      α-CH.sub.3                                                                    0.54  1.9    2.0                                  19     H       Et     H     --    --     <<80.sup.c                           15a    H       Et     α-CH.sub.3                                                                    --    --     <<10.sup.c                           23     Δ.sup.16                                                                           H       0.26  0.81   1.0                                    RU-486            0.28.sup.d                                                                            0.87.sup.d                                                                             .sup. 1.0.sup.d                            ______________________________________                                         .sup.a From % Inhib = a + b · ln dose                                .sup.b Actual dose giving ≧ 90% inhibition                             .sup.c No inhibition at tested dose                                           .sup.d Results variable. These data from "best run".                     

                  TABLE 3                                                         ______________________________________                                        Oral Antiprogestational Activity                                              (Anti-Clauberg) of 17α-Acetoxy-6α-methyl-11β-                (4,N,N-dimethylaminophenyl)-19-nor-pregna-                                    4,9-diene-3,20-dione (15)                                                                Total SC                                                               Total  Dose of                                                                Oral   Proges-            McPhail                                             Dose   terone   Wt of Uterus                                                                            Index   %                                       N.sup.a                                                                           (mg)   (mg)     (g ± SD)                                                                             (0-4)   Inhibition.sup.b                        ______________________________________                                        6   0.0    0.0      1.98 ± 0.40                                                                          0       --                                      6   0.0    0.8      3.06 ± 0.45                                                                          3.96 ± 0.04                                                                        --                                      6   1.0    0.8      3.26 ± 0.34                                                                          3.46 ± 0.12                                                                        12.7 ± 3.0                           6   5.0    0.8      2.14 ± 0.22                                                                          1.92 ± 0.48                                                                        51.6 ± 12.2                          5   10.0   0.8      2.24 ± 0.27                                                                          1.30 ± 0.24                                                                        67.2 ± 6.1                           ______________________________________                                         .sup.a Number of rabbits.                                                     .sup.b Based on change in McPhail Index.                                 

                  TABLE 4                                                         ______________________________________                                        PROGESTATIONAL ACTIVITY                                                       (MCGINTY ASSAY)                                                                ##STR6##                                                                                     McPhail Index                                                                       Right Horn                                                                              Left Horn                                     R       Dose (μg)  (Control) (Treated)                                     ______________________________________                                        H       2.0           0         3.0 ± 0.32                                         4.0           0         3.7 ± 0.12                                         8.0           0         3.6 ± 0.10                                 α-CH.sub.3                                                                      20.0          0         3.8 ± 0.12                                         40.0          0         3.9 ± 0.12                                         80.0          0         3.8 ± 0.12                                 ______________________________________                                    

Example 11. Progestational Activity in Vivo

The 16α-ethyl compounds which showed no antiprogestational activity wereexamined for progestational activity in the intrauterine assay. In thisassay estrogen-primed immature female rabbits are treated by injectionof the test compound into the left horn of the uterus while the righthorn is left untreated as a control. Each horn is then scored forendometrial proliferation by the McPhail Index. As Table 4 shows, thesecompounds were potent progestational agents. This is a totallyunexpected result, since all examples of prior art known to theinventors show that compounds which bind to the progesterone reeptor andcontain an 11β-(4-N,N-dimethylaminophenyl)-substituent exhibitantiprogestational activity. It indicates a possible need forreassessment of the current hypotheses regarding the effect of thissubstituent on antagonist versus agonist activity.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the present claims, theinvention may be practiced otherwise than as specifically describedherein.

What is claimed as new and desired to be secured by Letters Patent ofthe United States is:
 1. An 11β-aryl-19-norprogesterone of the formula:##STR7## wherein R¹ is OC(O)CH₃, or OC(O)R⁵, wherein R⁵ is C₂₋₈ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl or aryl, F² is H, R³ is H, C₁₋₄ alkyl, C₂₋₄alkenyl, or C₂₋₄ alkynyl, R⁴ is H, CH₃, F or Cl, or R⁶ is H, (CH₃)₂ N,CH₃ O, CH₃ CO, CH₃ S, CH₃ SO, CH₃ SO₂, and X is O or NOCH₃.
 2. Thenorprogesterone of claim 1, wherein R⁶ is N,N-dimethylamino or acetyl.3. The norprogesterone of claim 1, wherein R⁴ is hydrogen or methyl andR¹ is acetoxy.
 4. The norprogesterone of claim 2, wherein saidnorprogesterone is17α-acetoxy-6α-methyl-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione,17α-acetoxy-11β-(4N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione,17α-acetoxy-11β-(4-acetylphenyl)-19-norpregna-4,9-diene-3,20-dione.
 5. Amethod of inducing an anti-glucocorticoid antihormonal response,comprising administering to a human or non-human mammal in need thereof,an anti-glucocorticoid effective amount of a norprogesterone of claim 1,said norprogesterone having a binding affinity for the glucocorticoidreceptor and having anti-glucocorticoid activity in said human ornon-human mammal.
 6. The method of claim 5, wherein said effectiveamount is a unit dose between 0.1 milligram and 1.0 gram.
 7. The methodof claim 5, wherein said human or non-human mammal exhibits Cushing'ssyndrome or glaucoma.
 8. A method of inducing a progestational hormonalresponse, comprising administering to a human or non-human mammal inneed thereof, a progestional effective amount of a norprogesterone ofclaim 1, said norprogesterone having a binding affinity for theprogesterone receptor and possessing progestational activity in saidhuman or non-human mammal.
 9. The method of claim 8, wherein saideffective amount is a unit dose between 0.1 milligram and 1.0 gram. 10.A method of inducing an anti-progestational response in a human ornon-human mammal, comprising administering to a human or non-humanmammal in need thereof, an anti-progestational effective amount of anorprogesterone of claim 1, said norprogesterone having a bindingaffinity for the progesterone receptor and possessinganti-progestational activity in said human or non-human mammal.
 11. Themethod of claim 10, wherein said effective amount is a unit dose between0.1 milligram and 2.0 grams.
 12. A method of inducing a progestationalhormonal response, comprising administering to a human or non-humanmammal in need thereof, a progestational effective amount of thenorprogesterone of claim 1, said norprogesterone having a bindingaffinity for the progesterone receptor and possessing progestationalactivity in said human or non-human mammal.
 13. An11β-aryl-19-norprogesterone of the formula: ##STR8## wherein R³ is H,C₁₋₄ alkyl, C₂₋₄ alkenyl or C₂₋₄ alkynyl, R⁴ is H, CH₃, F or Cl, R⁶ isH, (CH₃)₂ N, CH₃ O, CH₃ CO, CH₃ S, CH₃ SO, CH₃ SO₂, and X is O or NOCH₃.14. The norprogesterone of claim 13, wherein R⁶ is N,N-dimethylamino oracetyl.
 15. The norprogesterone of claim 13, wherein saidnorprogesterone is11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9,16-triene-3,20-dione or11β-(4-acetylphenyl)-19-norpregna-4,9,16-triene-3,20-dione.
 16. A methodof inducing a progestational hormonal response, comprising administeringto a human or non-human mammal in need thereof, a progestional effectiveamount of a norprogesterone of claim 13, said norprogesterone having abinding affinity for the progesterone receptor and possessingprogestational activity in said human or non-human mammal.
 17. Themethod of claim 16, wherein said effective amount is a unit dose between0.1 milligram and 1.0 gram.
 18. A method of inducing ananti-glucocorticoid antihormonal response, comprising administering to ahuman or non-human mammal in need thereof, an anti-glucocorticoideffective amount of the norprogesterone of claim 13, saidnorprogesterone having a binding affinity for the glucocorticoidreceptor and having anti-glucocorticoid activity in said human ornon-human mammal.
 19. A method of inducing an anti-progestationalresponse in a human or non-human mammal comprising administering to ahuman or non-human mammal in need thereof, an anti-progestationaleffective amount of the norprogesterone of claim 13, saidnorprogesterone having a binding affinity for the progesterone receptorand possessing anti-progestational activity in said human or non-humanmammal.
 20. An 11β-aryl-19-norprogesterone having the formula: ##STR9##wherein R¹ and R³ taken together are --CH₂ -- or --N═N--CH₂ --, R² is H,R⁴ is H, CH₃, F or Cl, R⁶ is H, (CH₃)₂ N, CH₃ O, CH₃ CO, CH₃ S, CH₃ SO,CH₃ SO₂ and X is O or NOCH₃.
 21. The norprogesterone of claim 20,wherein R⁴ is hydrogen or methyl and R⁶ is dimethylamino or acetyl. 22.A method of inducing a progestational hormonal response, comprisingadministering to a human or non-human mammal in need thereof, aprogestational effective amount of the norprogesterone of claim 20, saidnorprogesterone having a binding affinity for the progesterone receptorand possessing progestational activity in said human or non-humanmammal.
 23. The method of claim 22, wherein said effective amount is aunit dose between 0.1 milligram and 1.0 gram.
 24. A method of inducingan anti-glucocorticoid antihormonal response, comprising administeringto a human or non-human mammal in need thereof, an anti-glucocorticoideffective amount of the norprogesterone of claim 20, saidnorprogesterone having a binding affinity for the glucocorticoidreceptor and having anti-glucocorticoid activity in said human ornon-human mammal.
 25. A method of inducing an anti-progestationalresponse in a human or non-human mammal comprising administering to ahuman or non-human mammal in need thereof, an anti-progestationaleffective amount of the norprogesterone of claim 20, saidnorprogesterone having a binding effinity for the progesterone receptorand possessing anti-progestational activity in said human or non-humanmammal.
 26. An 11α-aryl-19-norprogesterone having the formula: ##STR10##wherein R¹ is H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, OH, OC(O)CH₃,or OC(O)R⁵, wherein R⁵ is C₂₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl oraryl, R⁴ is H, CH₃, F or Cl, R⁶ is H, (CH₃)₂ N, CH₃ O, CH₃ CO, CH₃ S,CH₃ SO, CH₃ SO₂, and X is O or NOCH₃.
 27. The norprogesterone of claim26, wherein R¹ is acetoxy or C₂₋₈ alkynyl, R⁴ is hydrogen or methyl andR⁶ is dimethylamino or acetyl.
 28. A method of inducing a progestationalhormonal response, comprising administering to a human or non-humanmammal in need thereof, a progestational effective amount of thenorprogesterone of claim 26, said norprogesterone having a bindingaffinity for the progesterone receptor and possessing progestationalactivity in said human or non-human mammal.
 29. The method of claim 28,wherein said effective amount is a unit dose between 0.1 milligram and0.1 gram.
 30. A method of inducing an anti-glucocorticoid antihormonalresponse, comprising administering to a human or non-human mammal inneed thereof, an anti-glucocorticoid effective amount of thenorprogesterone of claim 26, said norprogesterone having a bindingaffinity for the glucocorticoid receptor and having anti-glucocorticoidactivity in said human or non-human mammal.
 31. A method of inducing ananti-progestational response in a human or non-human mammal comprisingadministering to a human or non-human mammal in need thereof, ananti-progestational effective amount of the norprogesterone of claim 26,said norprogesterone having a binding affinity for the progesteronereceptor and possessing anti-progestational activity in said human ornon-human mammal.